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Department of Experimental Pathology, St. Bartholomew’s and The Royal London School of Medicine and Dentistry, London, United Kingdom
Genetic knock-out in mice of peroxisome proliferator-activated
receptor-
(PPAR) can prolong inflammation in response to
leukotriene B4. Although cyclooxygenase 2 has been
shown to be induced by PPAR activation, the effect of PPAR agonists on
the key inflammatory enzyme systems of nitric oxide synthase (NOS) and
stress proteins has not been investigated. The effect on these of
naturally occurring eicosanoid PPAR agonists (leukotriene
B4 and
8(S)-hydroxyeicosatetraenoic acid, which are
PPAR selective; PGA2, PGD2,
PGJ2, and 
12PGJ2, which are
PPAR
selective) and the synthetic PPAR agonist Wy14,643 was
examined in activated RAW264.7 murine macrophages. Leukotriene
B4 and
8(S)-hydroxyeicosatetraenoic acid stimulated
nitrite accumulation, indicative of enhanced NOS activity.
PGA2, PGD2, PGJ2,
12PGJ2, and Wy14,643 reduced nitrite
accumulation, with 12PGJ2 being the most
effective. The mechanism behind this reduction was examined using
Western blotting. Inhibition of nitrite accumulation was associated
with a fall in inducible NOS protein and an induction of heme oxygenase
1, correlating both dose dependently and temporally. Other proteins
examined (cyclooxygenase 2, heme oxygenase 2, heat shock protein 70,
and glucose-regulated protein 78) were unaffected. The data suggest
that naturally occurring PPAR agonists can inhibit the inducible NOS
enzyme pathway. This inhibition may be mediated by modulation of the
stress protein, heme oxygenase 1. Thus, the generation of eicosanoid
breakdown products during inflammation may contribute to its eventual
resolution by activation of the PPAR system. This system may thus
represent a novel target for therapeutic intervention in inflammatory
disease.
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T. Claudel, M. D. Leibowitz, C. Fievet, A. Tailleux, B. Wagner, J. J. Repa, G. Torpier, J.-M. Lobaccaro, J. R. Paterniti, D. J. Mangelsdorf, et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor PNAS, February 27, 2001; 98(5): 2610 - 2615. [Abstract] [Full Text] [PDF]
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